CN104208687A - Dry powder inhalation pharmaceutical composition containing different active components packaged in inhalation device for synchronous application - Google Patents
Dry powder inhalation pharmaceutical composition containing different active components packaged in inhalation device for synchronous application Download PDFInfo
- Publication number
- CN104208687A CN104208687A CN201310205299.XA CN201310205299A CN104208687A CN 104208687 A CN104208687 A CN 104208687A CN 201310205299 A CN201310205299 A CN 201310205299A CN 104208687 A CN104208687 A CN 104208687A
- Authority
- CN
- China
- Prior art keywords
- pharmaceutical composition
- epinephrine
- glucocorticoid
- broxaterol
- medicine
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Landscapes
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention relates to a drug for treating respiratory tract diseases especially asthma, and especially relates to a dry powder inhalation pharmaceutical composition containing different active components, which are individually packaged and placed in an inhalation device for synchronous application, such as glucocorticoid, epinephrine beta2-acceptor stimulant, and the like.
Description
Technical field:
The medicine, particularly different activities composition that the present invention relates to treatment respiratory tract disease especially asthma are packed and the dry powder Inhaled pharmaceutical composition simultaneously used at a suction apparatus respectively.
Background technology:
Asthma is a kind of chronic airway inflammation, it is characterized by Reversible airway obstruction and airway reactivity increases, and the secretions that airway obstruction is caused by bronchial mucosa inflammation increases, myxedema and inflammatory stimulus smooth muscle spasm two kinds of factors cause; And airway reactivity to increase also be the result of the bronchial epithelial cell damage caused due to airway inflammation.People recognize, only have the inflammation controlling airway mucus, just can reach the object finally reducing airway hyperreactivity, relieving asthma symptoms.The compound medicine of the medicine of the pulmonary disease such as current treatment asthma commonly glucocorticoid and epinephrine broxaterol, as budesonide formoterol powders for inhalation, salmaterol fluticasone propionate powders for inhalation etc., such compound medicine achieves fabulous curative effect in the treatment, has obvious advantage compared with glucocorticoid or epinephrine broxaterol folk prescription medicine.
But glucocorticoid is different from the micromeritics characteristic of epinephrine broxaterol, using dosage also exists larger different, and above-mentioned situation is more complicated under adjuvant exists.Such as aborning in fill to the process in same container because micromeritics characteristic difference keeps the higher uniformity, there is larger difficulty.
Summary of the invention:
In order to ensure the uniformity of compound medicine, retain the curative effect of compound medicine simultaneously, we find that the different activities composition of compound dry powder Inhaled pharmaceutical composition is packed and in the process simultaneously used at a suction apparatus respectively, medicine still can produce same effect, better medicaments uniformity degree is provided,, be surprised to find that this mode can better ensure medicine Emptying Rate in production with in storing, and the stability of medicine also increases simultaneously.
The invention provides following technical scheme.
A kind of compound dry powder Inhaled pharmaceutical composition be made up of glucocorticoid, epinephrine broxaterol, pharmaceutic adjuvant that one or more are applicable to inhalation, it is characterized in that glucocorticoid, epinephrine broxaterol and corresponding excipient substance barrier packaging respectively thereof, and be stored in a suction apparatus.This device can for the device introduced in Chinese patent ZL201080031347.2.
Aforementioned pharmaceutical compositions, is characterized in that one or more that described glucocorticoid is selected from ciclesonide, fluticasone, mometasone, budesonide, beclometasone or its ester.
Aforementioned pharmaceutical compositions, is characterized in that described epinephrine broxaterol is one or more in albuterol, terbutaline, fenoterol, procaterol, formoterol, salmaterol, bambuterol, zilpaterol, Mabuterol, western Boot sieve, bromine Boot sieve, Afromoterol, QAB-149 and officinal salt thereof.
Above-mentioned pharmaceutical composition, is characterized in that described epinephrine broxaterol is the one in salbutamol sulfate, terbutaline sulphate, tartaric acid Afromoterol, maleic acid QAB-149, formoterol fumarate, SALMETEROL XINAFOATE, maleic acid QAB-149.
Aforementioned pharmaceutical compositions, it is characterized in that the glucocorticoid of described active component and epinephrine broxaterol are micropowder, the particle diameter of micropowder is 0.5 ~ 10 μm.
Aforementioned pharmaceutical compositions, is characterized in that described pharmaceutic adjuvant comprises carrier and additives, and the particle diameter of described carrier is 20 ~ 60 μm, and preferable particle size is 30 ~ 60 μm.Carrier is one or more in carbohydrate carrier, aminoacid, lecithin or phosphatidylcholine.Described aminoacid is glycine, valine, leucine.Described saccharide is one or more of monosaccharide, disaccharide or its derived carbohydrate, and derived carbohydrate refers to that the straight or branched hydrocarbon chain of involved 20 carbon atoms at the most of at least one hydroxyl on glycan molecule replaces.Described monosaccharide is mannitol, fructose, glucose.Described disaccharide is maltose, trehalose, cellobiose, lactose, sucrose.Described derived carbohydrate is eight acetate fiber two sugar esters, sucrose octa-acetate, eight acetic acid lactose esters, five acetic acid glucose esters, six acetic acid Nitranitols and eight acetic acid Sargassum sugar esters.Preferred vector is lactose, and described lactose is alpha-lactose monohydrate, β-Lactis Anhydrous, one or more in amorphous spray-dried lactose, crystallizing and drying lactose, and described lactose is more preferably crystallizing and drying lactose.
Described pharmaceutical composition, is characterized in that additives are one or more in surfactant, lubricant, antistatic additive.
Surfactant is poloxamer.Lubricant is one or more in magnesium stearate, micropowder silica gel, Pulvis Talci.
The summation of active component and the weight ratio of carrier are 1:5 ~ 100.
Aforementioned pharmaceutical compositions, the method for micronization of described active component adopts spray drying method, fluid bed supersonic jet mill method, speed lapping method, ball-milling method, fluid energy mill method or solvent method.
Aforementioned pharmaceutical compositions, is characterized in that glucocorticoid single using dosage is 50-500 μ g, epinephrine broxaterol single using dosage 1-100 μ g.
Should be appreciated that because known reason, as the retention of active component in suction apparatus, the amount of often kind of active component that patient sucks can be different from the amount of metering.Therefore the applicating ratio between active component can be different from the ratio of metering.The ratio preferably used is in the described metered proportions indicated.
Particle diameter in the present invention is as being D99 mass median diameter (mass mean diameter) without refering in particular to, and this particle diameter is the particle diameter corresponding when reaching 99% of the cumulative particle sizes percentile detecting a sample by laser particle analyzer.
Detailed description of the invention
Micronization of the present invention can use known mechanical crushing method or spray drying method.Mechanical crushing method refers to and utilizes the method for fluid energy mill respectively active component and carrier powder to be broken into required particle diameter.Spray drying method refers to and ciclesonide or carrier is dissolved in organic solvent entirely as in ethanol, through spray dryer, solid material is made required particle diameter.Use during spray drying method and can also add surfactant as poloxamer etc.
Capsule type dry powder inhalant can adopt No. 3 plant capsules (sino-america joint-venture Suzhou Capsule Co., Ltd produces, trade name: Vcaps), and each embodiment feeds intake according to 1000 capsules.The capsule loading bubble-cap type of powder spray is aluminum-plastic packaged, takes out, load powder spray inhaler (Shanghai balance pharmaceutical factory) and use during use.
The mixed method of compound medicine: the medicine that the amount of the medicine that taken amount is little and equivalent is large, be placed in blender to mix simultaneously, then add with the large drug dilution of the amount of mixture equivalent even, till times amount like this is increased to and adds the large component of whole amount, mixing, the time of each mixing is 10 minutes.
The method (equal increments method) that medicine mixes with adjuvant: the adjuvant component of get it filled thing and equivalent, be placed in blender to mix simultaneously, add again and dilute evenly with the adjuvant component of mixture equivalent, till times amount like this is increased to and adds whole supplementary material component, mixing, the time of each mixing is 10 minutes.
Mixing machinery adopts FGD stationary hopper mixer (sky, Shanghai nine enginerring works).
In following embodiment, bitubular suction apparatus is the device introduced in Chinese patent ZL201080031347.2.
Monotubular suction apparatus is the KRT-D01 type inhaler that Tai'an Kai Rui extra high molecular company limited produces.
Medicine assay method: budesonide, momestasone furoate, fluticasone propionate, formoterol fumarate, SALMETEROL XINAFOATE sulfur are according to the method for American Pharmacopeia 34 editions, beclometasone, salbutamol sulfate, terbutaline sulphate are according to the method for Chinese Pharmacopoeia 2010 editions, and ciclesonide, fluticasone furoate replace the analytical method of blocking identical with budesonide, propanoic acid fluorine respectively.
Embodiment 1
Glucocorticoid, epinephrine broxaterol are pulverized respectively, particle diameter sees the following form, medicine after pulverizing is that 20 times of weight lactoses of 30 μm mix according to the method described above respectively with mean diameter, according to glucocorticoid 100 μ g/ grain, the standard fill medicament capsule of epinephrine broxaterol 10 μ g/ grain, aluminium foil blister is packed, and often kind of medicine is got 10 and measured medicament contg, is designated as 0 day numerical value.Often kind of medicine is got 100 and is preserved under temperature 30 ± 2 DEG C, relative humidity 65 ± 5% condition and get 10 capsules at random after 6 months and again measure medicament contg, Emptying Rate, the uniformity afterwards, is designated as 6 months numerical results and sees the following form.
Cloud test method: detect according to Chinese Pharmacopoeia 2010 editions two annex XE " Content uniformity test ".
Emptying Rate assay method: detect according to Chinese Pharmacopoeia 2010 editions two annex 13 pages " Emptying Rate inspection technique ".
Comparative examples 1
Glucocorticoid, the epinephrine broxaterol pulverized in Example 1, particle diameter sees the following form, medicine after pulverizing mix homogeneously according to the method described above, be that 20 times of weight lactoses of 30 μm mix according to the method described above afterwards with mean diameter, according to glucocorticoid 100 μ g/ grain, the standard fill medicament capsule of epinephrine broxaterol 10 μ g/ grain, aluminium foil blister is packed, often kind of compound medicine is got 10 and is measured medicament contg, is designated as 0 day numerical value.Often kind of medicine is got 100 and is preserved under temperature 30 ± 2 DEG C, relative humidity 65 ± 5% condition and get 10 capsules at random after 6 months and again measure medicament contg, Emptying Rate, the uniformity afterwards, is designated as 6 months numerical result conditions and sees the following form.
Embodiment 2
Glucocorticoid, epinephrine broxaterol are pulverized respectively, particle diameter sees the following form, medicine after pulverizing is that 20 times of weight lactoses of 45 μm mix according to the method described above respectively with mean diameter, according to glucocorticoid 100 μ g/ grain, the standard of epinephrine broxaterol 10 μ g/ grain is inserted in bitubular suction apparatus.
Embodiment 3
Glucocorticoid, epinephrine broxaterol are pulverized respectively, particle diameter sees the following form, medicine after pulverizing is that 10 times of weight lactoses of 60 μm mix according to the method described above respectively with mean diameter, inserts in bitubular suction apparatus according to the ratio of single administration amount (unit) Chinese medicine in following table.
| Embodiment code name | Medicine name | Particle diameter (μm) | Weight (μ g/ unit) |
| 3-1 | Budesonide | 4.4 | 50 |
| Formoterol fumarate | 6.5 | 2 | |
| 3-2 | Momestasone furoate | 3.3 | 100 |
| Formoterol fumarate | 7.5 | 5 | |
| 3-3 | Ciclesonide | 2.7 | 200 |
| Formoterol fumarate | 8.5 | 10 | |
| 3-4 | Fluticasone propionate | 5.8 | 200 |
| SALMETEROL XINAFOATE | 5.1 | 50 | |
| 3-5 | Fluticasone furoate | 6.6 | 200 |
| SALMETEROL XINAFOATE | 2.9 | 50 | |
| 3-6 | Beclometasone | 7.4 | 400 |
| Salbutamol sulfate | 5.8 | 100 | |
| 3-7 | Momestasone furoate | 1.3 | 100 |
| Terbutaline sulphate | 2.7 | 100 |
Embodiment 4
Glucocorticoid, epinephrine broxaterol are pulverized respectively, particle diameter sees the following form, medicine after pulverizing is that 20 times of weight lactoses of 20 μm mix according to the method described above respectively with mean diameter, according to glucocorticoid 100 μ g/ grain, the standard of epinephrine broxaterol 20 μ g/ grain is inserted in bitubular suction apparatus.
Embodiment 5
Glucocorticoid, epinephrine broxaterol are pulverized respectively, particle diameter sees the following form, according to glucocorticoid 100 μ g/ grain after medicine after pulverizing mixes according to the method described above with adjuvant respectively, the standard of epinephrine broxaterol 10 μ g/ grain is inserted in bitubular suction apparatus.
Pharmacological Examples 1 asthma pharmacological evaluation
1, animal model
Choose healthy male Wistar rat (there is antibacterial to checking out, the rat of bacteriological infection will not select), body weight is 200 ± 10g, put into the bell glass of about 5 liters, spray into 3% chlorination second phthalein choline and 0.1% histamine phosphate's volume mixed liquor 15 second with the pressure of 400mmHg.After spraying stops, observing the asthmatic latent period (namely asthma occur, breathe be the devil, until twitch time of falling) of rat, draw and breathe heavily the rat that the latent phase is less than 70 seconds or is greater than 120 seconds and will not select.
2, experimental technique
Learn from else's experience and measure the qualified rat of asthmatic latent period, random packet is carried out according to the group in following table, often organize 10, every day carries out administration in the bell glass of about 5 liters, simultaneously experimental group is loaded in bitubular suction apparatus by the medicine in embodiment to give 2 kinds of medicines according to inhalation route, model group 1 gives according to inhalation route the Lactis Anhydrous that mean diameter is 55 μm, dosage is 5mg/Kg, comparative examples group medicine is loaded conventional monotubular suction apparatus inhalation route and gives corresponding dosage compound medicine by matched group, within the 4th day of administration, give 0.3% 2 hydrochloric acid histamine when spraying after after giving whole medicine 1.5 hours, observe the change (draw animal when breathing heavily and do not occur in 6 minutes that to breathe heavily the volt phase be calculate for 360 seconds to the person of falling to draw) of asthmatic latent period and tic incidence rate before and after drug.
Dosage in experimental group, matched group is all as the criterion with glucocorticoid medicine dosage.
3, experimentation and result: animal generation asthma until the time of falling of twitching see the following form.
Have multiple form to be the result of this experiment in the present embodiment, problem for convenience of explanation, splits experimental result.
Table 1-1 comparative examples experimental result (n=10, mean ± SD)
Difference is not had afterwards before administration by the asthmatic latent period of T testing identity asthmatic model animal by above-mentioned experimental data, basically identical with not administration group, can illustrate that asthmatic model animal only gives anti-bacterial drug, cannot Paroxysmal asthma be extended.
Table 1-2 embodiment experimental result (n=10, mean ± SD)
In sum, can illustrate due under Different Package form by embodiment 1 and the contrast of comparative examples 1, the uniformity of compound medicine, content, Emptying Rate all have obvious difference, that separately packs is better than hybrid packed form, and can illustrate under Different Package form by embodiment 2 and the contrast of comparative examples 1, the curative effect of compound medicine is similar to, but separately packaging be slightly better than hybrid packed form.
Claims (10)
1. the compound dry powder Inhaled pharmaceutical composition be made up of glucocorticoid, epinephrine broxaterol, pharmaceutic adjuvant that one or more are applicable to inhalation, it is characterized in that glucocorticoid, epinephrine broxaterol and corresponding excipient substance barrier packaging respectively thereof, and be stored in a suction apparatus.
2. pharmaceutical composition as claimed in claim 1, is characterized in that one or more that described glucocorticoid is selected from ciclesonide, fluticasone, mometasone, budesonide, beclometasone or its ester.
3. pharmaceutical composition as claimed in claim 1, is characterized in that described epinephrine broxaterol is one or more in albuterol, terbutaline, fenoterol, procaterol, formoterol, salmaterol, bambuterol, zilpaterol, Mabuterol, western Boot sieve, bromine Boot sieve, Afromoterol, QAB-149 and officinal salt thereof.
4. pharmaceutical composition as claimed in claim 1, it is characterized in that the glucocorticoid of described active component and epinephrine broxaterol are micropowder, the particle diameter of micropowder is 0.5 ~ 10 μm.
5. pharmaceutical composition as claimed in claim 1, is characterized in that described pharmaceutic adjuvant comprises carrier and additives.
6. pharmaceutical composition as claimed in claim 5, is characterized in that the particle diameter of described carrier is 20 ~ 60 μm.
7. pharmaceutical composition as claimed in claim 5, is characterized in that described carrier is one or more in carbohydrate carrier, aminoacid, lecithin or phosphatidylcholine.
8. pharmaceutical composition as claimed in claim 5, is characterized in that additives are one or more in surfactant, lubricant, antistatic additive.
9. pharmaceutical composition as claimed in claim 1, the method for micronization of described active component adopts spray drying method, fluid bed supersonic jet mill method, speed lapping method, ball-milling method, fluid energy mill method or solvent method.
10. pharmaceutical composition as claimed in claim 1, is characterized in that glucocorticoid single using dosage is 50-500 μ g, epinephrine broxaterol single using dosage 1-100 μ g.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310205299.XA CN104208687A (en) | 2013-05-29 | 2013-05-29 | Dry powder inhalation pharmaceutical composition containing different active components packaged in inhalation device for synchronous application |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310205299.XA CN104208687A (en) | 2013-05-29 | 2013-05-29 | Dry powder inhalation pharmaceutical composition containing different active components packaged in inhalation device for synchronous application |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN104208687A true CN104208687A (en) | 2014-12-17 |
Family
ID=52090859
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201310205299.XA Pending CN104208687A (en) | 2013-05-29 | 2013-05-29 | Dry powder inhalation pharmaceutical composition containing different active components packaged in inhalation device for synchronous application |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN104208687A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108721219A (en) * | 2017-11-15 | 2018-11-02 | 沈阳药科大学 | A kind of bioadhesive lung inhales Nano Composite Particles and preparation method thereof |
| CN108771761A (en) * | 2018-08-16 | 2018-11-09 | 上海方予健康医药科技有限公司 | A kind of glucocorticoid and β2The preparation process of the compound dry powder inhalation of receptor stimulating agent |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20030075172A1 (en) * | 2001-10-19 | 2003-04-24 | Johnson Keith A. | Method and apparatus for dispensing inhalator medicament |
| CN101756942A (en) * | 2008-12-25 | 2010-06-30 | 天津金耀集团有限公司 | Oral lung inhalation aerosol powder |
| CN102470224A (en) * | 2009-07-16 | 2012-05-23 | 创新生物医疗有限公司 | Improvements in or relating to dry powder inhalers |
-
2013
- 2013-05-29 CN CN201310205299.XA patent/CN104208687A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20030075172A1 (en) * | 2001-10-19 | 2003-04-24 | Johnson Keith A. | Method and apparatus for dispensing inhalator medicament |
| CN101756942A (en) * | 2008-12-25 | 2010-06-30 | 天津金耀集团有限公司 | Oral lung inhalation aerosol powder |
| CN102470224A (en) * | 2009-07-16 | 2012-05-23 | 创新生物医疗有限公司 | Improvements in or relating to dry powder inhalers |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108721219A (en) * | 2017-11-15 | 2018-11-02 | 沈阳药科大学 | A kind of bioadhesive lung inhales Nano Composite Particles and preparation method thereof |
| CN108771761A (en) * | 2018-08-16 | 2018-11-09 | 上海方予健康医药科技有限公司 | A kind of glucocorticoid and β2The preparation process of the compound dry powder inhalation of receptor stimulating agent |
| CN108771761B (en) * | 2018-08-16 | 2021-12-14 | 上海方予健康医药科技有限公司 | Glucocorticoid and beta2Preparation process of compound dry powder inhalant of receptor agonist |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US9549936B2 (en) | Method for preparing dry powder for inhalation formulation comprising salmeterol xinafoate, fluticasone propionate and tiotropium bromide | |
| KR101853997B1 (en) | Use of glycopyrrolate for treating tachycardia | |
| EP3957301A1 (en) | Ultra low density pulmonary powders | |
| US20170281529A1 (en) | Formulations | |
| JP2016515640A (en) | Composition comprising at least two dry powders obtained by spray drying to improve the stability of the formulation | |
| CN109464429B (en) | Inhalation pressure quantitative aerosol pharmaceutical composition and preparation method thereof | |
| US20140314684A1 (en) | Medicinal aerosol formulations | |
| CN107205936B (en) | Composition comprising at least one dry powder obtained by spray drying for increasing the stability of the formulation | |
| CN104208687A (en) | Dry powder inhalation pharmaceutical composition containing different active components packaged in inhalation device for synchronous application | |
| Salama et al. | Concurrent oral and inhalation drug delivery using a dual formulation system: the use of oral theophylline carrier with combined inhalable budesonide and terbutaline | |
| CN104208688A (en) | Pharmaceutical composition containing individually-packaged mometasone furoate and epinephrine beta2-acceptor stimulant placed in inhalation device for synchronous application | |
| CN104208690A (en) | Pharmaceutical composition containing individually-packaged ciclesonide and epinephrine beta2-acceptor stimulant placed in inhalation device for synchronous application | |
| WO2009052624A9 (en) | Inhalation compositions comprising montelukast acid and a pde-4 inhibitor or an inhaled corticosteroid | |
| CN104208689A (en) | Pharmaceutical composition containing individually-packaged budesonide and epinephrine beta2-acceptor stimulant placed in inhalation device for synchronous application | |
| CN104208686A (en) | Pharmaceutical composition containing individually-packaged fluticasone and epinephrine beta2-acceptor stimulant placed in inhalation device for synchronous application | |
| CN104208701A (en) | Compound inhalation preparation containing antifungal drug | |
| ITMI20130571A1 (en) | PHARMACEUTICAL COMPOSITION CONTAINING BUDESONIDE AND FORMOTEROL | |
| CN104208045A (en) | Compound inhalation preparation containing penicillin antibiotic and glucocorticoid | |
| EP4149422A1 (en) | Inhalable lactose containing composition | |
| CN104208060A (en) | Compound inhalation preparation containing penicillin antibiotic | |
| US11786460B2 (en) | Pharmaceutical dry powder composition for inhalation comprising a thyroid hormone | |
| CN105616390B (en) | The application of pulullan polysaccharide and derivative in preparation slow release drug granule | |
| CN104208046A (en) | Carbapenem antibiotic inhalation preparation | |
| CN115154442A (en) | Preparation method of powder inhalation for Reidesvir | |
| CN105078982A (en) | Method for preparing salbutamol compound inhalation aerosol |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20141217 |
|
| WD01 | Invention patent application deemed withdrawn after publication |